Impact of hippocampal neuronal ablation on neurogenesis and cognition in the aged brain

Abstract

Neuronal loss is the most common and critical feature of a spectrum of brain traumas and neurodegenerative disorders such as Alzheimer's disease (AD). The capacity to generate new neurons in the central nervous system diminishes early during brain development and is restricted mainly to two brain areas in the mature brain: subventricular zone and subgranular zone. Extensive research on the impact of brain injury on endogenous neurogenesis and cognition has been conducted primarily using young animals, when neurogenesis is most active. However, a critical question remains to elucidate the effect of brain injury on endogenous neurogenesis and cognition in older animals, which is far more relevant for age-related neurodegenerative disorders such as AD. Therefore, we examined the impact of neuronal loss on endogenous neurogenesis in aged animals using CaM/Tet-DTA mice, a transgenic model of hippocampal cell loss. Additionally, we investigated whether the upregulation of adult neurogenesis could mitigate cognitive deficits following substantial hippocampal neuronal loss. Our findings demonstrate that aged CaM/Tet-DTA mice that sustain severe neuronal loss exhibit an upregulation of endogenous neurogenesis. However, despite this significant upregulation, neurogenesis alone is not able to mitigate the cognitive deficits observed. Our studies suggest that the aged brain has the capacity to stimulate neurogenesis post-injury; however, multiple therapeutic approaches, including upregulation of endogenous neurogenesis, will be necessary to recover brain function after severe neurodegeneration.

Keywords: 5-bromo-2-deoxyuridine; 5-ethynyl-2-deoxyuridine; AD; Alzheimer’s disease; BrdU; CE; CamKIIα; DCX; DG; DPX; DT(A); EdU; NSCs; PBS; SGZ; SVZ; TBI; TBS-T; TRE; Triton X-100; Tween-20–Tris-buffered saline; Tx-100; calcium-calmodulin kinase II alpha; coefficient of error; dentate gyrus; diphtheria toxin A chain; doublecortin; hippocampus; mixture of distyrene (a polystyrene), a plasticizer (tricresyl phosphate), and xylene; neural stem/progenitor cells; neurodegenerative disorders; neurogenesis; neuronal loss; phosphate-buffered saline; subgranular zone; subventricular zone; tTA; tetracycline-controlled transcriptional activator; tetracycline-responsive element; traumatic brain injury.